Mutations in the insulin or insulin-like growth factor receptor (Daf-2) of the worm Caenorhabditis elegans substantially enhance the life span of the animals. This occurs, at least in part, because the mutant animals have enhanced resistance to various forms of stress. Indeed, Henis-Korenblit et al. found that daf-2 mutants were more resistant than wild-type animals to toxic substances that cause misfolding of proteins in the endoplasmic reticulum (ER). When such unfolded proteins are detected in the ER, the ER stress response—a signaling process through which transcription is altered to regulate production of proteins that coordinate protection of proteins in the ER and removal of damaged proteins—ensues. A main mechanism that mediates this transcriptional activation in cells experiencing ER stress is provided by the alternative splicing—and consequent production of an activated form—of a transcription factor called XBP-1 (X-box–binding protein-1). However Henis-Korenblit found that daf-2 mutant animals had lower, rather than higher, amounts of the spliced XBP-1 mRNA. They interpreted this to mean that the animals had lower amounts of ER stress and thus had a lower “set point” for activation of XBP-1 and its normal transcriptional targets and that XBP-1 might instead regulate new targets in the daf-2 mutants. They then searched for genes regulated in an XBP-1–dependent manner in daf-2 mutants and identified dox-1. The Dox-1 protein has not been characterized, but from its sequence, it is predicted to function in splicing or processing of RNA. Furthermore, expression of dox-1 was coordinately regulated by XBP-1 and DAF16 (a FOXO transcription factor family member activated in daf-2 mutants), and dox-1 appears to have binding sites in its promoter for both XBP-1 and DAF16. Genetic evidence indicated that Dox-1 contributes to longevity of daf-2 mutants in a manner independent of ER stress, even though it is regulated by XBP-1. Thus, in animals with low signaling through the insulin and insulin-like growth factor receptor, the ER stress response protein XBP-1 appears to take on a new role, cooperating with other transcription factors to enhance longevity.